This proposal is for ongoing study of ways to improve cerebral protection during operations on the heart and great vessels which require arrest of antegrade circulation. Clinical and experimental data suggest that subtle cerebral injury occurs if the duration of hypothermic circulatory arrest (HCA) is more than 30 minutes even under optimal circumstances, and some complex procedures cannot reliably be completed in so short a time. In our porcine experimental model, the effect of strategies such as retrograde cerebral perfusion (RCP) can be studied to see whether they can be used to extend the safe duration of HCA to 60 minutes. In this clinically relevant model, the effect of changes in the implementation of HCA and RCP on cerebral blood flow, cerebral metabolism, intracranial pressure, electrophysiological recovery, behavioral outcome (including preservation of ability to learn conditioned reflexes) and cerebral histopathology can be used to see whether new approaches, such as use of lower temperatures, postoperative ultrafiltration, cold reperfusion, and treatment with various pharmacological agents are likely to improve neurological outcome after operations requiring HCA. The hypothesis that some of the cerebral injury following HCA/RCP is occurring as a consequence of apoptosis, or programmed cell death, opens up the possibility of arresting this suicidal cascade using specific inhibitors of the proteases and endonucleases which participate in this process as well as inhibitors of protein synthesis, all of which have had dramatic success in reducing injury in rodent models of cerebral ischemia. The results of this study will make a significant contribution toward improving long-term outcome of complex surgery on the heart and great vessels in both infants and adults.